CMSC-ACTRIMS: Cutting Quinidine Still Works in Combo Med

Action Points

Explain to interested patients that current treatment of pseudobulbar affect carries some risk of cardiac side effects.

Explain that lowering the dose of quinidine in the current treatment may improve safety without decreasing effectiveness.

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

SAN ANTONIO -- Low-dose quinidine in combination with dextromethorphan reduces the frequency of uncontrollable laughing or crying in multiple sclerosis while improving patient safety, according to research presented here.

Using just a third of the quinidine dose contained in the current combination therapy, marketed as Zenvia, reduced those episodes by more than half, compared with a decrease of about one a day with placebo (P=0.0280), Daniel Wynn, MD, of Consultants in Neurology in Northbrook, Ill., and colleagues found.

Pseudobulbar affect (PBA), characterized by laughing or crying outbursts incongruent with the patient's emotional state, affects 15% of patients with MS, and is also seen in ALS, Alzheimer's disease, and other neurologic diseases.

"Pseudobulbar affect causes considerable distress for patients and caregivers," Wynn told attendees at the meeting of the Joint Consortium of Multiple Sclerosis Centers and America's Committee on Treatment and Research in Multiple Sclerosis. "It can be extremely socially disabling, and it is often under-recognized and undertreated."

Previous studies established that 30 mg of dextromethorphan in combination with 30 mg of quinidine effectively treated the condition, leading to FDA approval of the combination therapy. "The efficacy was extremely well established in previous trials," Wynn said. But ongoing concerns about the adverse effects of quinidine prompted researchers to try a reduced dose for an improved safety profile.

Dextromethorphan is an NMDA receptor antagonist as well as a sigma receptor agonist, and is responsible for the drug's clinical benefit. Quinidine is a CYP2D6 inhibitor, added to prevent metabolism of dextromethorphan. High doses of quinidine are associated with prolongation of the QT interval.

The dose in the current trial, 10 mg, "is truly miniscule," Wynn said.

To determine if the reduced dose was still effective for PBA, Wynn and colleagues enrolled 326 patients, including 129 with MS, at 64 centers in three countries.

Patients were randomized 1:1:1 to either the standard dose of dextromethorphan 30 mg and 10 mg of quinidine, a lower dextromethorphan dose of 20 mg and the 10 mg of quinidine, or placebo, twice a day for 12 weeks.

The primary outcome variable was change in the number of laughing or crying episodes per day. Secondary outcomes included change in the Center for Neurologic Studies Lability Scale (CNS-LS), and a pain score.

At baseline, MS patients averaged between three and four episodes of laughing or crying per day.

Active treatment with the higher dose dextromethorphan and the low dose of quinidine reduced those episodes by 2.7 per day, compared with just over one per day for MS patients receiving placebo (P=0.0280).

There was no significant effect from lower-dose dextromethorphan, but there was a trend for superiority when both active treatment groups were compared together against placebo.

The CNS-LS score in MS patients was also improved by the 30 mg dextromethorphan/10 mg quinidine dose versus placebo, falling by approximately 50% in active-treatment patients versus 33% in placebo patients.

Change on pain score was not significantly different between groups, but a post-hoc analysis of MS patients with significant baseline pain indicated that the high-dose, but not low-dose dextromethorphan improved pain relative to placebo.

Dizziness, diarrhea, headache, and nasopharyngitis were more common in MS patients receiving active treatment. More patients in the 30 mg/10 mg treatment group completed the trial than in the other two groups.

"Results from this study reproduce the strong efficacy of earlier trials," Wynn said, while improving safety and tolerability.

"Despite the relatively small sample size of this study's MS subpopulation," Wynn said, the high-dose dextromethorphan combined with low-dose quinidine "was found to be significantly superior to placebo for decreasing PBA episode rate."

He noted that further studies are warranted to evaluate the treatments effects on pain in MS.

"Having a drug that is tolerable to patients is as important as efficacy," said Corey Ford, MD, of the University of New Mexico Health Sciences Center in Albuquerque, and past-president of the CMSC. "Improving tolerability is likely to increase the treatment's usefulness to patients."

A low-quinidine dose formulation of Zenvia is currently under consideration by the FDA for approval.

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